Preparation and method for obtaining relief from coughing



United States This invention relates to an improved preparation and method for obtaining relief from coughing in human bemgs.

It is an object of the present invention to provide a preparation and method of the above character which gives both immediate and also relatively long-range relief from coughing.

The coughing reflex is generally caused by the stimulus of irritation of the mucous membrane of the respiratory tree resulting from colds and other upper respiratory infections, allergies, and foreign bodies or irritants. Cough relief preparations, such as syrups and cough drops, which are commonly available, contain topical agents to soothe and relieve the irritation of the mucous membrane and are effective only while the soothing action is taking place. In the case of a persistent irritation, the coughing accordingly resumes as soon as the topical agent disappears from the affected membrane. As a result, cough preparations of this type which depend upon the action of topicals remedies do not afford sustained relief from coughing.

Recognizing this situation, attempts have heretofore been made to obtain more long-range relief by using sedatives and narcotics, such as chloroform or codeine. These preparations are not satisfactory since the sedatives and narcotics are habit-forming and have undesirable side effects or do not adequately suppress the coughing reflex when administered in safe unit dosage quantities.

It is an object of the present invention to overcome the difliculties and disadvantages heretofore encountered, and to provide an improved preparation and method for obtaining relief from coughing, which will not only afford immediate relief from coughs resulting from irritations of the mucous membrane but will also suppress the coughing reflex for a relatively prolonged period of time so as to give sustained relief from coughing.

A further object is the provision of an improved preparation and method of the above character for relief from coughing which will not have undesirable side effects upon either the central nervous system or other organs of the patient.

In accordance with one aspect of our invention, we provide a suitable vehicle either in liquid form, such as a syrup, or in solid form, such as a lozenge or cough drop, which includes a topical or local agent for soothing or pacifying the mucous membrane which will afford immediate relief from the irritation while in contact therewith; and which also includes an improved anti-tussive agent operating upon the central and peripheral action centers for coughs of the nervous system of the patient to suppress the response to the irritation and control the cough reflex.

The vehicle employed may, of course, be varied considerably. Where the preparation is to be supplied in liquid form, the vehicle should include a suitable solvent which is non-toxic to a human being and which is compatible with the other ingredients employed. For this purpose, we may employ water, ethyl alcohol, glycerine, sorbitol, proplene glycol, or various alkaline or acidified mixtures thereof.

Mixed with the solvent are suitable flavoring and coloring materials and a topical or local agent for soothing and pacifying the mucous membrane. In many instances, the flavoring materials serve also as topical agents which atent ice will soothe the mucous membrane. Thus, sugar and various fruit extracts, such as cherry, orange, lemon, or lime extract, serve both as flavoring materials and as soothing agents. Other topical soothing agents, such as glycerine, sorbitol, propylene glycol, or various syrups such as simple syrup, white pine syrup, or fruit syrup may also be added. In this connection, various non-toxic nauseants, and expectorants such as ammonium chloride, potassium guaiacolsulfonate, ipecacuanha, tartar emetic, squills, ammonium carbonate, and iodides of various alkalies, may be added, which serve as topical or local agents since they stimulate the flow of bronchial secretion, which in turn serves to soothe the mucous membrane.

Other active or flavoring materials, such as citric acid or other organic acids, amines or their salts, such as lemonorange glycerides (bioflavonoid), ascorbic acid and caramel, may be added.

The coloring materials employed should be edible and non toxic and compatible with the other ingredients and for this purpose, we may employ such coloring agents as brilliant blue, amaranth, charcoal and certified food coloring, such as orange No. 7, red No. 2, etc.

The proportions of these ingredients, serving as flavoring, coloring, and soothing agents in the carrying vehicle, are not critical. Thus, the flavoring material should be proportioned to taste and the coloring material to appear ance. Suflicient soothing agents should be employed so as to give topical or local relief to the irritation of the mucous membrance, when administered in reasonable dosage units. The quantity of solvent employed should be sufficient so that the syrup or liquid preparation will readily flow without adhering unduly to the surfaces of the container, spoons, and other utensils and at the same time maintaining a sufficiently concentrated solution to permit the soothing agent to adhere to the irritated portions of the mucous membrance.

The percentage of water and other solvents, including any of the alcohols, may be varied between approximately 20 percent and 99 percent by weight of the complete preparation. These percentages are to include and solvent used in the flavoring extracts and also any water combined with sugar or oxygen derivatives used in the preparation of this kind of syrup. The percentage of sugar or other oxygen derivatives when used may be varied between approximately 5 percent and 79 percent by weight, and the percentage of other soothing agents when used between approximately 0.2 percent and 15 percent by weight. Other flavoring materials may be added in quantities to suit the taste, and coloring materials may be added in quantities to obtain the desired appearance.

As previously indicated, we add to the mixture of carrying vehicles and other ingredients an anti-tussive agent operating upon the central and peripheral action centers for coughs of the nervous system to suppress the response to the irritation and to control the cough reflex. For this purpose, we employ an improved anti-tussive agentin the form of certain indole alkaloid extracts of plants of the genus Rauwolfia and also of the genus Gelsemium and possible other sources from succulent plants such as yucca, fungi, etc. together with their salts and also synthetic and natural reproductions thereof of the type which will act upon the central and peripheral action centers for coughs of the nervous system to suppress the response to the irritation and to control the cough reflex and at the same time will not cause undesirable side efiects on the central nervous system or on the other organs of the body nor cause the release of serotonin by the body tissue. We have found that the following indole alkaloid extracts of Rauwolfia and Gelsemium may be employed:

(1) The indole alkaloids which are yellow colored, strong anhydronium bases and the salts thereof. These bases are characterized by being of aromatic ionic form and having a pKa of between 10.4 and 11. Representative of this group of indole alkaloids are serpentine, serpentinine, alstonine, and sempervirine. Serpentine, ser- Specific examples of liquid preparations, such as cough syrups, embodying our invention are as follows:

Example 1 The following ingredients were thoroughly mixed together to produce a liquid preparation for relief from coughing, which soothes the mucous membrane of the respiratory tree and also operates on the central and peripheral action centers for coughs of the nervous sys- The usefulnessof tertiary indole alkaloids'seems to be enhanced where ring E is highly hydroxylate'd. An ex-' ample of a tertiary indole alkaloid of this type is isoraunescine. All of the tertiary indole alkaloids indicated above areextracts of plants of the genus Rauwolfia.

In addition to the indole alkaloids listed above under 1 and 2, we may also employ the non-toxic compatible salts, such as the nitrate, chloride, acetate and other organic or inorganic salts. The salts may be prepared either by reacting the acid with the alkaloid or by double decomposition with other salts. In addition to using the natural indole E akaloid extracts of Rauwolfia and Gel-.

semium and the salts thereof, We may employfsynthetic' and natural reproductions thereof.

While all of the above-indicated indole alkaloids may; be employed, we prefer to employ serpentine and the salts of serpentine and more particularly we prefer to employ.

serpentine nitrate. We havefound that very satisfactory anti-tussive effects are obtained from preparations containing serpentine nitrate without any undesirable 'side effects or toxicity and without the release of serotonin by the body tissue.

i The anti-tussive agent is mixed with the other ingredi-.

cuts in the preparation. The proportion of the autitussive agent can, of course, be varied. However, we have found that desirable anti-tussiye effects are obtained by administering unit dosages oi the indicated alkaloids of between 0.01 mg. and 0.1 mg. "Accordingly, the percentage. of anti-tussive agent in the liquid preparation should be con- ';trolled so-that the indicated quantity is present in the desired unit dosage of the preparation. Generally speaking, the desired unit dosage Will he a teaspoonful or' t-ablespoon-fulandjthe. quantity or percentage caught:

ides-ages" of. one teaspoonful:

tem' to suppress the cough reflex.

Approximate percentage or parts by weight Ingredients:

Water 31.726482 Ethyl alcohol c 4.0 Sugars (sucrose, dextrose, levulos'e) 60.0 Wild cherry extract 3.51 Citric acid 0.715 Ammonium chloride 0.0286 Caramel 0.0143

Amaranth 0.004 Brilliant blue 0.000118 'Serpen-tine nitrate -l. 0.0015

After the ingredients are thoroughly mixed together, the preparation is readyto be orally administered to a human being. In'this connection, the proportions are such that inunit dosages of one teaspoonful (approximately 5.0 cc), approximately 0.09 mg. of the antitussive agent will be present and will provide the desired eifect upon the central and peripheral action centers for coughs of the nervous system. Thus, the liquid cough preparation will provide both immediate and relatively long-range relief from coughing.

The preparation may be suitably packaged and may be stored for relatively long periods of time for later use without. deterioration. g

It will be appreciated that the percentages of ingredients may be varied within the ranges indicated above and that other vehicles, flavoring, coloring and topical agents may be substituted for the ones specifically listed. Thus, the percentage of serpentine nitrate may be varied between 0.00015 and 0.0015 percent by weight of the mixture. In addition, other indole alkaloids and salts thereof of the type indicated, which are non-toxic and. do not cause the release of serotonin, may be substituted for theserpentine nitrate.

i Example II.

The following ingredients were thoroughly mixed togetherjto produce a liquidpreparation for relief from coughing, which soothes the mucous membrane of the respiratory tree and also operates on the central and peripheral action centers for cough of the nervous system to suppress the cough reflex.

' Approximate percentage After 'thefingredients are thoroughly mixed-together, the preparation is ready to ee orally administered to a human being. In this connection, the proportions are such that'in unit dosages of one teaspoonful' (approximately 5.0. c9), approximately 0.05 mg of the 'anti-tussive agent will'be'present and will provide the desired efiect upon the central and peripheral action centers for coughs of the nervous'systeni. Thus, the liquid cough preparation will provide both immediate and relatively long-range relief from coughing.

The preparation may be suitably packaged and may be stored for relatively long periods of time for later use without deterioration.

. It will be appreciated that the percentages of ingredients may be varied within the ranges indicated above and that other vehicles, flavoring, coloring, and topical agents may be substituted for the ones specifically listed. Thus, the percentage of reserpinine may be varied between 0.00015 and 0.0015 percent by weight of the mixture. In addition, other iudole alkaloids and salts thereof of the type indicated, which are non-toxic and do not cause the release of serotonin, may be substituted for the reserpinine.

Liquid preparations indicated in the above examples are particularly intended for oral administration. In addition, liquid preparations may be provided for direct hypodermic injection into the blood stream. For this purpose, only a liquid vehicle, such as water, physiological saline solution, or the like is mixed with the anti-tussive agent Of the above type. The proportion of anti-tussive agent to liquid may be varied but should be such that in conven tional injection dosages, between 0.01 and 0.1 mg. of the anti-tussive agent are present. We have found that satisfactory results are obtained by utilizing unit injection dosages containing approximately 0.05 mg. per unit dosage.

As previously indicated, our improved preparation for relief from coughing may also be provided in solid form, such as a tablet, lozenge, or cough drop. In preparing tablets or cough drops, standard hard candy-making pro cedures or cold-press tableting processes may be followed.

A cough drop should contain a suitable carrying vehicle, flavoring materials, coloring materials if desired, a topical or local soothing agent, and an anti-tussive agent of the above-indicated type, which operates upon the central and peripheral action centers for coughs of the nervous system. Sugar serves satisfactorily as a vehicle or carrying agent, as well as a flavoring agent. Various other flavoring agents, such as fruit extracts of the type indicated above, namely, cherry, orange, lemon or lime extract, licorice, and citric acid may also be added. Caramel may also be used both as a coloring and flavoring agent, and other coloring agents, such as amaranth, brilliant blue, charcoal and certified food coloring may be used also. The sugar and the other flavoring agents serve satisfactorily as topical soothing agents, and other soothing agents may also be added, such as glycerine, ammonium chloride, potassium guaiacolsulfonate, sorbitol, propylene glycol, and the like.

A concentrated syrup is prepared from the sugar and it is cooked to a temperature of between 265 and 350 F. It is then partially cooled to a temperature of between 200 and 250 F. and the other ingredients, including an anti-tussive agent of the type indicated above which opcrates upon the central and peripheral action centers for coughs of the nervous system to suppress the cough reflex, are mixed therewith. The percentage of ingredients may be considerably varied, but we have found that satisfactory results are obtained by using between 97 percent and 98 percent by weight of sugars and between 1 and 2 percent by weight of other soothing agents where employed. Other flavoring materials may be added in quantities to suit the taste, and the coloring materials are added in quantities to obtain the desired appearance. Sufficient anti-tussive agent of the type indicated should be added so as to provide between 0.01 and 0.1 mg, preferably 0.05

mg, in each dosage unit or cough drop.

We have found that where cough drops of the conventional size are prepared, the desired results are obtained by adding between 0.0005 and 0.005 percent by weight of the anti-tussive agent to the mixture.

The partially cooled mixture is then poured into molds to provide cough drops of the desired size and shape.

6' 1 A specific example of one method of making a cough drop embodying our invention is as follows:

Example 111 Ingredients? of total mixture Licorice 0.4

Charcoal 0.8 Essential oils 0.25 Serpentine nitrate 0.0025

After the ingredients have been thoroughly mixed, the mixture is then cooled and formed into cough drops of approximately 2.16 grams in weight. The cough drops thus prepared each contain approximately 0.05 mg. of serpentine nitrate. drops give topical relief by soothing the mucous membrane of the respiratory tree and they also operate upon the central and peripheral action centers for coughs of the nervous system to suppress the cough reflex.

It should be understood that other flavoring, coloring, and topical agents may be substituted for those indicated in this example and that the percentage of ingredients may be varied as indicated.

In addition, other anti-tussive agents operating upon the central and peripheral action centers for coughs of the nervous system of the type indicated above, which will not cause undesirable side elfects and which will not cause the release of serotonin, may be substituted for serpentine nitrate and the percentage of anti-tussive agent may be varied within limits so that each cough drop has between 0.01 and 0.1 mg.

In addition to cough drops prepared by standard candymaking procedure, we may provide tablets prepared by cold-press tableting methods. A suitable binding material, such as starch, is employed; and sugar, flavoring materials, and topical agents may be added if desired, as Well as our improved anti-tussive agent. The ingredients are thoroughly mixed together, and sufiicient anti-tussive agent is added so that between 0.01 and 0.1 mg. will be present in each tablet. Unit quantities are then coldpressed into tablets of the desired size.

The tablets may be orally administered to give relief from coughing, and the anti-tussive agent will act upon the central and peripheral action centers for coughs of the nervous system to suppress the cough reflex.

It will thus be seen that we have provided an improved preparation and method for obtaining relief from coughing, which will give immediate relief by soothing the mucous membrane of the respiratory tree and will also give more long-range relief by operating upon the cough center of the nervous system.

Modifications may be made in the illustrated embodiments of our invention. Thus, under certain circumstances, sedatives and narcotics may also be included in our improved preparation and other active and inactive ingredients may also be added if desired.

We claim:

1. A preparation to be orally administered for obtaining relief from a persons coughing caused by irritations of the mucous membrane of the respiratory tree which comprises a carrying vehicle including a topical remedy for relieving irritations of the mucous membrane and an anti-tussive agent in the form of serpentine nitrate, said preparation being in unit dosage form with each dosage unit containing between 0.01 and 0.1 mg. of serpentine nitrate.

2. A preparation to be administered in unit dosage form for relief from a persons coughing which comprises a carrying vehicle having mixed therewith reserpinine in When administered orally, the cough 7 unit dosage quantities of between approximately 0.01 and 0.1 mg.

3. A preparation to be administered in unit dosage form for relief from a persons coughing which comprises 'aricine, isoreserpinine, reserpinine, serpentine, serpentinine, tetrahydroserpentine, sempervirine, a-yohimbine, isoraunicine, the salts thereof and mixtures thereof, said .preparation being administered in dosage units containing between approximately $.91 and 0-1 mg. of said antitussive agent which operates on the central and peripheral action centers for coughs of the: nervous system to suppress the cough reflex but wi-tl not cause undesirable side effects nor the release of serotonin by the body tissue.

5. The method for obtaining relief from'a persons coughing due to irritation of the respiratory tract which comprises orally administering to said person a preparation which includes a carrying agent and an anti-tussive agent in the form of serpentine nitrate in dosage units of between approximately 0.01 and 0.1 rug.

References Cited in the file of this patent Woodson: Rauwolfia, 1957, Little, Brown and Co., Boston, Mass, pp. 113-115 and 117.

U. S. Dispensatory, 25th Edition, 1955, Lippincott Co,

Philadelphia, Pa., pp. 1825-1828.

Dustan: Annals of N.Y. Academy of Sciences, vol. 59, April 30, 1954, pp- 138, 139. 

1. A PREPARATION TO BE ORALLY ADMINISTERED FOR OBTAINING RELIEF FROM A PERSON''S COUGHING CAUSED BY IRRITATIONS OF THE MUCOUS MEMBRANE OF THE RESPIRATORY TREE WHICH COMPRISES A CARRYING VEHICLE INCLUDING A TOPICAL REMODY FOR RELIEVING IRRITATIONS OF THE MUCOUS MEMBRANE AND AN ANTI-TUSSIVE AGENT IN THE FORM OF SERPENTINE NITRATE, SAID PREPARING BEING IN UNIT DOSAGE FORM WITH EACH DOSAGE UNIT CONTAINING BETWEEN 0.01 AND 0.1 MG OF SERPENTINE NITRATE. 